Point mutations of 3BP2 identified in human-inherited disease cherubism result in the loss of function
Point mutations of 3BP2 identified in human-inherited disease cherubism result in the loss of function
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DOI：
10.1111/j.1365-2443.2004.00784.x
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发表时间：
2004-11-01
期刊：
影响因子：
2.1
通讯作者：
Sada, K
中科院分区：
文献类型：
--
作者：
Miah, SMS;Hatani, T;Sada, K
衔接蛋白3BP2正调节高亲和力IgE受体（Fc ε RI）介导的肥大细胞脱粒活化。遗传学研究发现人类遗传性疾病巨像症3BP2基因点突变。颌骨巨颌症多发囊肿内充满活化的破骨细胞和基质细胞，包括肥大细胞。通过大鼠嗜碱性白血病RBL-2H3肥大细胞的过表达研究，我们分析了点突变对3BP2蛋白功能的影响，3BP2蛋白在Fc ε RI介导的肥大细胞活化中起正性调节作用。过表达3BP2突变体抑制抗原诱导的脱粒和细胞因子基因转录。在过表达3BP2的幼稚突变体的细胞中，抗原诱导的Vav 1磷酸化、Rac 1活化、细胞外信号调节激酶（ERK）、c-Jun N-末端激酶（JNK）、p38丝裂原活化蛋白激酶（MAPK）、核因子κ B激酶抑制剂（IKK）和活化T细胞核因子（NFAT）均受损。此外，3BP2的幼稚突变可能会消除与伴侣蛋白14 - 3 - 3相互作用的结合能力。这些结果表明，3BP2的突变形式的过表达抑制抗原诱导的肥大细胞活化。提示3BP2基因的点突变导致了3BP2在体内的功能障碍。
Adaptor protein 3BP2 positively regulates the high affinity IgE receptor (FcepsilonRI)-mediated activation of degranulation in mast cells. Genetic study identified the point mutations of 3BP2 gene in human-inherited disease cherubism. The multiple cysts in cherubism lesion of jaw bones are filled with the activated osteoclasts and stromal cells, including mast cells. By over-expression study using rat basophilic leukaemia RBL-2H3 mast cells, we have analysed the effect of the point mutations on the function of 3BP2 protein, which plays a positive regulatory role on FcepsilonRI-mediated mast cell activation. Over-expression of 3BP2 mutants suppressed the antigen-induced degranulation and cytokine gene transcription. Antigen-induced phosphorylation of Vav1, activation of Rac1, extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), p38 mitogen activated protein kinase (MAPK), inhibitor of nuclear factor kappaB kinase (IKK) and nuclear factor of activated T cells (NFAT) were all impaired in the cells over-expressing the cherubism mutants of 3BP2. Furthermore, cherubism mutations of 3BP2 may abrogate the binding ability to interact with chaperone protein 14-3-3. These results demonstrate that over-expression of the mutant form of 3BP2 inhibits the antigen-induced mast cell activation. It suggests that point mutations of 3BP2 gene cause the dysfunction of 3BP2 in vivo.